Acne vulgaris is perhaps the commonest disease of the skin. It is estimated that 85-90% of the population aged between 10-25 are affected. It is a disorder of the pilosebaceous unit, which consists of a sebaceous gland draining into a hair follicle via a sebaceous duct. These glands are particularly large and active on the forehead, nose, face, neck, and the front and back of the upper chest, and they are lined on the outside by a layer of basement membrane. What appears to happen when an ache is formed is that the cells at the periphery of the gland, that is, the cells just above the basement membrane, start to be filled with fat droplets. As these cells also serve the function of generating new cells, so, when new cells are generated, the original cells that are beginning to be filled with fat droplets are being displaced towards the center of the gland. And while they are being displaced towards the center, the fat droplets keep on increasing in size as more fat accumulates. When these cells rupture at around the center of the gland, they are but fat-droplets lined by a cell membrane. This resultant mixture of fat and cellular debris after the rupture is sebum. Normally, sebum is excreted to the skin surface via the sebaceous duct and the hair follicle. When the production of sebum is excessive, the skin will appear greasy. However, if the outflow of sebum is somehow obstructed by a narrowing or blockage of the ductal lumen as a result of hyperkeratinization of the ductal epithelium, a comedo, which is the primary lesion in acne vulgaris, is formed.
The causes of hyperkeratinization of the ductal epithelium and sebum production are at present not known. However, there is good evidence to show that hyperkeratinization, similar to sebum production, starts with accumulation of fat droplets in the horny layer of the ductal epithelium. This may well imply that these two processes go hand in hand.
Though the etiology of acne vulgaris is not know because the basic changes in hyperkeratinization and sebum production are not understood, it is generally believed that genetic, bacterial, climatic and psychological factors are involved. But by far the most important single factor connected with the pathogenesis of acne appears to be hormonal, though the evidences are quite circumstantial. For example, the evidences indicate that the disease process is most frequently seen during puberty and adolescence; that the disease process often shows cyclic exacerbations premenstrually; that during pregnancy, the disease process often gets worse; that eunuchs, or females having ovariectomy done before puberty, do not have acnes; that ACTH administration in susceptible individuals of any age produces acne; and that ovarian tumors and adrenal tumors may be associated with acne.
While these are good reasons to suggest that acne vulgaris is closely related to hormones, they are not solid evidences to prove that these hormones produce acne. In fact, there are many pitfalls in these arguments. There is no explanation, for example, as to why certain individuals have acnes, while others with exactly the same hormonal make-up do not have acnes. Explanation is again lacking as to why the disease process occurs mainly during puberty and adolescence, with the incidence falling off sharply after the early twenties. There is no evidence whatsoever to suggest that the hormonal make-up of an individual will change after that period.
Some suggest that the male hormones, the androgens, are a potent stimulant of sebum production, and are responsible for the production of acne. But the very fact that the incidence of acne vulgaris is the same in both sexes refutes the argument. Even in the face of this, some still suggest that the androgens are indeed important in the pathogenesis of acne, but it is not the absolute amount of androgens that is significant, but rather, the sensitivity of the sebaceous glands towards the action of the hormones is more crucial. However, information is lacking as to the factors affecting such sensitivity and the suggestion is purely speculative.
The cyclic premenstrual exacerbation and the worsening of the disease process during pregnancy are not adequately explained, it is known that there is a steady decrease in sebum production during the first half of the menstrual cycle; in the luteal phase the excretion rate rises, only to fall again just premenstrually. The increase in sebum production in the luteal phase, with the clinical manifestation of the "premenstrual flare" and the worsening of the disease process during pregnancy, coincide with a period of a huge increase in progesterone secretion, but there is apparently no explanation to correlate this increase in progesterone level and acne production.
Even though it has been observed that eunuchs and females having ovariectomy done before puberty do not have acne, no study has been conducted to show that administration of sex hormones in these subjects will produce acne.
The reason why only susceptible subjects develop acne after ACTH administration is again not adequately explained, it is not understood why certain subjects are not susceptible. And in those who do develop acne, it is not clear whether the acne is due to a direct action of ACTH on the sebaceous glands, or whether it is due to an increase in level of adrenocorticoids or an increase in androgens of adrenocortical origin subsequent to the administration of ACTH.
All these only serve to show that the argument that hormones are responsible for the etiology of acne is unjustifiable and weak. The situation is indeed very perplexing and the evidences conflicting. However, if the theory of hormones is scrutinized more carefully, it is interesting to note that all the hormones involved are derived from cholesterol, (with the exception of ACTH; but ACTH stimulates the production of adrenocorticoid steroids, so that the end result is still a production of hormones derived from cholesterol) whose primary building blocks are the acetates in the form of acetyl-Co A. And Coenzyme A (Co A) is well known for its importance and the strategic position it occupies in fatty acid metabolism. And if the etiology of ache vulgaris is viewed from this angle, taking into account some of the observations associated with the disease process, it may be possible to form a novelty idea as to its pathogenesis, a novelty idea to explain the apparently very baffling situation.
There is a good reason for ache to develop at puberty. At puberty, there is a huge increase in production of the sex hormones to cater for the development of the primary and secondary sex organs. The demand for acetates, the biological active form of which is acetyl-Co A, is much increased because the acetates are the building blocks of cholesterol, the precursor of all the sex hormones. This is tantamount to an increase in demand for Coenzyme A, which in turn is equivalent to an increase in demand for pantothenic acid. A certain amount of pantothenic acid in the body is being channeled off for this purpose. As suggested in U.S. Pat. No. 5,039,698 relating to weight control, the use of pantothenic acid in the synthesis of the sex hormones seems to override the use of pantothenic acid in the metabolism of fat. Therefore, unless there is an abundant supply of pantothenic acid in the body, the portion that is rationed towards fat metabolism will be curtailed drastically. Consequently, there is a relative deficiency in the metabolism of fat that is proportional to the relative deficiency of pantothenic acid, and fat begins to accumulate in the body. Here, nature chooses to deposit these unmetabolized fat in the sebaceous glands in the form of fat droplets. If the supply of pantothenic acid is grossly deficient, its role in the metabolism of fat will be cut back drastically, and a lot of unmetabolized fat will be deposited in the sebaceous gland with the eventual increase in sebum production and the formation of ache. This explains why the sex incidence of the disease process is about equal.
There is little research conducted to study on the absolute amount of sex hormones that are required for the development of the primary and secondary sexual characteristics in the male or in the female during puberty and adolescence. But it seems that a fair amount will be required. The fact that eunuchs and females with a prepuberty ovariectomy do not have aches suggests that in such instances, no sex hormones are secreted, with a consequence that a lot of pantothenic acid in the form of Coenzyme A will be spared to perform the less important function of fat metabolism, and very efficiently.
When the primary and secondary sexual characteristics are fully developed, in most instances in the mid to late teens, sex hormones and hence pantothenic acid requirements are less in demand. More pantothenic acid can be directed to discharge the function of fat metabolism, and the deficiency in fat metabolism becomes less and less significant. This is the reason why the incidence of the disease process drops rapidly after the late teens and the early twenties.
The same argument holds for the "premenstrual flare" during the latter part of the menstrual cycle. During that period, some pantothenic acid is diverted to perform the duty of progesterone synthesis, (the absolute amount of progesterones and estrogens secreted during this period is much more than the amount of estrogens and progesterones secreted in the follicular phase) resulting in an aggravation of the disease process.
The same explanation is true of pregnancy, ACTH administration, ovarian and adrenal tumors that are hormone-secreting. In certain such instances, the disease process can be really bad, almost uncontrolled. This is in line with the known fact that in some of these conditions, the amount of hormones produced can be very high, leading to an enormous shortening of supply of pantothenic acid towards fat metabolism.
It now seems clear that the basic pathology in the production of ache vulgaris is a shortening of supply of pantothenic acid. The role of the sex hormones in the pathogenesis is no longer perplexing. Its effect is mainly an indirect one. It is through a process of competitive inhibition of fat metabolism by vying with that process for the limited supply of pantothenic acid in the form of Coenzyme A. This explains why the effect of androgens and estrogens relating to acne vulgaris varies so much in different individuals, from the completely normal to the most severe form of acne, though the hormonal make-up in these people is probably similar. This is in accordance with the works of most investigators who found that boys with acne do not have higher testosterone levels than boys without acne. It is the availability of extra pantothenic acid in the body to discharge the duty of fat metabolism that is important. The question of sensitivity of the glands towards androgens, not to mention the factors affecting it, now seems irrelevant. The actions of contraceptive pills in the treatment of acne vulgaris is now obvious. It acts through the suppressant effect on ovulation, hence holding down the secretion of progesterone and sparing Coenzyme A for the metabolism of fat, and thus finally achieves a beneficial effect on the disease process. This also helps to explain the fact that progesterone has no effect on the treatment of ache, because administration of progesterone does not suppress the intrinsic secretion of the hormone, and lends no relief to the strained supply of Coenzyme A.
With all the evidences cited above, it is apparent that a deficiency in pantothenic acid must play a most important role in the pathogenesis of acne vulgaris. It has been explained above that an increase in synthesis of hormones that are derivatives of cholesterol and an increase in fat intake will proportionately deplete the body of pantothenic acid. But considering the strategic position pantothenic acid occupies in the metabolism of carbohydrate, fat and protein, and the myriad functions it has in the body, many of which are as yet poorly understood, chances are there must be a lot more of other conditions that are of higher priority than fat metabolism, that will consume considerable amount of pantothenic acid. And these conditions will, understandably, make the ache process worse. Perhaps psychological stress, so well known to make acne worse, falls into this category. So may be climatic factor and a lack of sleep, both of which may be considered as some form of stress. Acneigenic drugs and chemicals may also deplete a lot of pantothenic acid through some complicated detoxifying process. All these factors will make the disease process worse.
It has been mentioned earlier that the pathogenesis of acne vulgaris involves an increase in sebum secretion and an abnormal keratinization of the follicular epithelium, and that these two processes often go hand in hand. Indeed, there is good reason to believe that hyperkeratinization, like increased sebum secretion, is related to a deficiency in pantothenic acid leading to a deficiency in the mechanism of fat metabolism. One reason is that the very first sign of hyperkeratinization is an accumulation of fat droplets in the horny layer of the follicular epithelium, very similar to the accumulation of fat droplets in the sebaceous gland cells. The other reason is that structural lipids form an integral part of the cell membrane. Since it has been shown that increase in sebum secretion relates to a deficiency in the enzymic system of fat metabolism through a deficiency in pantothenic acid, it is not unreasonable to suspect that this deficiency in enzymic system of fat metabolism may alter the structural lipid of the cell membrane, ultimately leading to hyperkeratinization.
Another supporting evidence for this suggestion comes from the observation of an increase in pore size of the hair follicles, which is one of the very first signs of acne vulgaris. This is probably a physiological response to both an increase in sebum production and hyperkeratinization of the follicular ductal epithelium which will grossly narrow the lumen of the duct. Nature will try to offset the narrowing by a hypertrophy of the duct as a whole, resulting in a greatly enlarged pore size of the hair follicle. Administration of pantothenic acid has a striking effect on reducing the pore size of the hair follicle to its original minute size very early on, within just a few days of treatment. This suggests that pantothenic acid has its effect not only on sebum secretion, but that it probably has a direct effect on reversing the hyperkeratinization process, hence the already narrowed lumen is now wider. Consequently, the hypertrophic process is no longer necessary, and so is subsequently reversed. This is in contrast to what is seen when sebum of an acne lesion is being squeezed out of the follicle. There, despite an absence of sebum in the gland, the pore size of the hair follicle is unchanged. It remains large because the root of the trouble is not tackled.
If acne vulgaris bears such a close relationship to fat metabolism, it is only natural to investigate whether other vitamins, aside from pantothenic acid, playing their roles as coenzymes in the metabolic processes of fat metabolism, will affect the pathological process. Fat metabolism, like other metabolic processes in the body, is extremely complicated and involves many sets of interrelated enzyme systems, and in many instances, merges with carbohydrate and protein metabolism. It is, therefore, difficult to pinpoint exactly the enzyme systems, together with their coenzymes, that are directly involved in fat metabolism. However, it is generally believed that the vitamins nicotinic acid and biotin, playing their roles as coenzymes in various metabolic processes, are heavily involved in fat metabolism. And it has been shown in the present invention that administration of these two vitamins together with pantothenic acid will have a synergistic effect on the disease process.